Dasatinib, with the trade name SPRYCEL™, is a oral tyrosine kinase inhibitor and developed by BMS Company. It is used to cure adult chronic myelogenous leukemia (CML), acute lymphatic leukemia (ALL) with positive Philadelphia chromosome, etc. Its chemical name is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl]amino]-5-thiazolformamide and its chemical structure is as following:

Five polymorphs of Dasatinib and the preparation methods thereof were described by Bristol-Myers Squibb in the Chinese Patent Application No. CN200580011916.6 (publication date is 13 Jun. 2007). The preparation methods instructed in this document are:
Monohydrate: Dasatinib (48 g) was added into ethanol (1056 mL 22 ml/g) and water (144 mL), and dissolved by heating to 75° C.; the mixture was purified, filtrated and transferred to the receiver. The solution reactor and transferring pipes were washed with the mixture of ethanol (43 mL) and water (5 mL). The solution was heated to 75˜80° C. to be soluble completely and water (384 mL) was heated and the temperature of the solution was kept between 75° C. and 80° C. The seed crystal of monohydrate (preferable) was added when cooling to 75° C., and keep the temperature at 70° C. for 1 h; cooling to 5° C. within 2 h and keeping the temperature at 0˜5° C. for 2 h. The slurry was filtrated and the filter cake was washed by the mixture of ethanol (96 mL) and water (96 mL); after being dried under vacuum≦50° C. 41 g of solid was obtained.
Butanol solvate: under refluxing (116° C.˜118° C.), Dasatinib was dissolved in 1-butanol (about 1 g/25 mL) to yield crystalline butanol solvate of Dasatinib. When cooling, this butanol solvate was recrystallized from solution. The mixture was filtrated and the filter cake was dried after being washed with butanol.
Ethanol solvate: 5D (4 g, 10.1 mmol), 7B (6.6 g, 50.7 mmol), n-bubanol (80 mL) and DIPEA (2.61 g, 20.2 mmol)) were added into a 100 ml round flask. The obtained slurry was heated to 120° C. and kept the temperature for 4.5 h, and then cooled to 20° C. and stirred over night. The mixture was filtrate, and the wet filter cake was washed with n-butanol (2×10 mL) to yield white crystal product. The obtained wet filter cake was put back to the 100 ml reactor and 56 mL (12 mL/g) of 200 proof ethanol was added. Then additional ethanol (25 mL) was added at 80° C., and water (10 mL) was added into the mixture to make it dissolved rapidly. Heat was removed and crystallization was observed at 75° C.˜77° C. The crystal slurry was further cooled to 20° C. and filtrated. The wet filter cake was washed with ethanol:water (1:1, 10 mL) once and then washed with n-heptane (10 mL) once. After that it was dried under the condition of 60° C./30 in Hg for 17 h to yield 3.55 g of substance only containing 0.19% water.
Neat form of N-6: DIPEA (155 mL, 0.89 mmol) was added into the mixture of compound 5D (175.45 g, 0.445 mol) and hydroxyethylpiperazine (289.67 g, 2.225 mol) in NMP (1168 mL). The suspension was heated at 110° C. for 25 min to be solution, which was then cooled down to about 90° C. The obtained solution was added dropwise into hot water (80° C., 8010 mL), and the mixture was stirred at 80° C. with heat preservation for 15 min and cooled to room temperature slowly. The solid was filtrated under vacuum and collected, washed by water (2×1600 mL) and dried under vacuum at 55° C.˜60° C. to give 192.45 of compound.
Neat form of T1H1-7 (neat form and pharmaceutically acceptable carrier): monohydrate of Dasatinib was heated over dehydrate temperature to yield.
Because Dasatinib is practically insoluble in water or organic solvent (e.g. methanol, ethanol, propanol, isopropanol, butanol, pentanol, etc.), even in the condition of heating, a large amount (over 100 times) of solvent is needed, which is disadvantageous in industrial production; in addition, with the method described in the Patent document of CN200580011916.6, the related substances in products can not be lowed effectively during the process of crystal preparation to improve the products quality.
In terms of polymorphs of drug, each polymorph has different chemical and physical characteristics, including melting point, chemical stability, apparent solubility, rate of dissolution, optical and mechanical properties, vapor pressure as well as density. Such characteristics can directly influence the work-up or manufacture of bulk drug and formulation, and also affect the stability, solubility and bioavailability of formulation. Consequently, polymorph of drug is of great importance to quality, safety and efficacy of pharmaceutical preparation. When it comes to Dasatinib, there are still needs in the art for new polymorphs suitable for industrial production and with excellent physical and chemical properties as well.